SUMMARY OF WORK The ultimate goals of this project are to determine how arterial stiffness properties influence myocardial structure and function and contribute to cardiovascular morbidity and mortality. A. We have recently discovered, in cross-sectional studies, that estrogen replacement therapy (ERT) in postmenopausal women reduced BP and the age-associated increase in arterial stiffness and that the addition of progestins to ERT appeared to reduce these beneficial effects. ERT has also been found to reduce longitudinal changes in SBP. This reduction of the longitudinal increase in SBP exerted by ERT was more pronounced in older postmenopausal women, and in those with lower BMI. B. To examine the role of nitric oxide (NO) synthesis on blood pressure changes during salt loading in postmenopausal women, we measured asymmetric dymethylarginine (ADMA), a potent endogenous inhibitor of NO synthesis before and after 4-7 days of low-salt (70mEg/day) or high-salt (260mEg/day) diet in 12 nonsensitive postmenopausal women. Sodium sensitivity of 24 hour ambulatory SBP and pulse pressure correlated with change in AD as A from low- to high- salt intake, after adjustment for age. These findings suggest that inhibition of NO synthesis contributes to the BP increase during high salt intake in postmenopausal women. C. To determine whether growth hormone or sex steroid supplementation ameliorates arterial stiffness properties in older adults with deficiencies of these substances, we measured pulse wave velocity and AGI in men and women aged 65 years and older, before and after hormonal replacement. D. We are testing the hypothesis that 1-2 years of home-based aerobic exercise training can reduce arterial stiffness in the multicenter NIH-sponsored Activities Counseling Trial of 810 subjects 35-75 years old. E. To determine whether aerobic exercise training can reduce the elevated arterial stiffness of older heart failure patients, we will measure arterial stiffness and peak VO2 before and after a 3 month program of aerobic training. F. A multicenter study to determine whether arterial stiffness is an independent risk factor for cardiovascular events in elderly free-living persons has been initiated. G. Arterial stiffness will be measured in the Pittsburgh, PA site for the Cardiovascular Health Study. Long-term follow-up of this cohort will allow us to examine the prognostic significance of arterial stiffness in an older population. H. A multicenter study has been initiated in which The collagen crosslink-breaking compound ALT-711 previously shown to reduce arterial stiffness in monkeys, is being given to mildly hypertensive human subjects for eight (8) weeks to determine its effects on arterial stiffness and ventricular structure and function. I. We are attempting to identify genetic factors contributing to exaggerated arterial stiffness and arterial intima -medial thickness in a Sardinian population (a "founder population", relatively genetically homogenous compared to "outbred" populations) and to determine whether these factors enhance the predictive accuracy for overall cardiovascular risk, when added to a standard cardiovascular risk profile.